Friday, September 07, 2012

More Expert Opinion on Junk DNA from Scientists

The Nature issue containing the latest ENCODE Consortium papers also has a New & Views article called "Genomics: ENCODE explained" (Ecker et al., 2012). Some of these scientist comment on junk DNA.

For exampleshere's what Joseph Ecker says,
One of the more remarkable findings described in the consortium's 'entrée' paper is that 80% of the genome contains elements linked to biochemical functions, dispatching the widely held view that the human genome is mostly 'junk DNA'. The authors report that the space between genes is filled with enhancers (regulatory DNA elements), promoters (the sites at which DNA's transcription into RNA is initiated) and numerous previously overlooked regions that encode RNA transcripts that are not translated into proteins but might have regulatory roles.
And here's what Inês Barroso, says,
The vast majority of the human genome does not code for proteins and, until now, did not seem to contain defined gene-regulatory elements. Why evolution would maintain large amounts of 'useless' DNA had remained a mystery, and seemed wasteful. It turns out, however, that there are good reasons to keep this DNA. Results from the ENCODE project show that most of these stretches of DNA harbour regions that bind proteins and RNA molecules, bringing these into positions from which they cooperate with each other to regulate the function and level of expression of protein-coding genes. In addition, it seems that widespread transcription from non-coding DNA potentially acts as a reservoir for the creation of new functional molecules, such as regulatory RNAs.
If this were an undergraduate course I would ask for a show of hands in response to the question, "How many of you thought that there did not seem to be "defined gene-regulatory elements" in noncoding DNA?"

I would also ask, "How many of you have no idea how evolution could retain "useless" DNA in our genome?" Undergraduates who don't understand evolution should not graduate in a biological science program. It's too bad we don't have similar restrictions on senor scientists who write News & Views articles for Nature.

Jonathan Pritchard and Yoav Gilad write,
One of the great challenges in evolutionary biology is to understand how differences in DNA sequence between species determine differences in their phenotypes. Evolutionary change may occur both through changes in protein-coding sequences and through sequence changes that alter gene regulation.

There is growing recognition of the importance of this regulatory evolution, on the basis of numerous specific examples as well as on theoretical grounds. It has been argued that potentially adaptive changes to protein-coding sequences may often be prevented by natural selection because, even if they are beneficial in one cell type or tissue, they may be detrimental elsewhere in the organism. By contrast, because gene-regulatory sequences are frequently associated with temporally and spatially specific gene-expression patterns, changes in these regions may modify the function of only certain cell types at specific times, making it more likely that they will confer an evolutionary advantage.

However, until now there has been little information about which genomic regions have regulatory activity. The ENCODE project has provided a first draft of a 'parts list' of these regulatory elements, in a wide range of cell types, and moves us considerably closer to one of the key goals of genomics: understanding the functional roles (if any) of every position in the human genome.
The problem here is the hype. While it's true that the ENCODE project has produced massive amounts of data on transcription binding sites etc., it's a bit of an exaggeration to say that "until now there has been little information about which genomic regions have regulatory activity." Twenty-five years ago, my lab published some pretty precise information about the parts of the genome regulating activity of a mouse hsp70 gene. There have been thousands of other papers on the the subject of gene regulatory sequences since then. I think we actually have a pretty good understanding of gene regulation in eukaryotes. It's a model that seems to work well for most genes.

The real challenge from the ENCODE Consortium is that they question that understanding. They are proposing that huge amounts of the genome are devoted to fine-tuning the expression of most genes in a vast network of binding sites and small RNAs. That's not the picture we have developed over the past four decades. If true, it would not only mean that a lot less DNA is junk but it would also mean that the regulation of gene expression is fundamentally different than it is in E. coli.



[Image Credit: ScienceDaily: In Massive Genome Analysis ENCODE Data Suggests 'Gene' Redefinition.

Ecker, J.R., Bickmore, W.A., Barroso, I., Pritchard, J.K. (2012) Genomics: ENCODE explained. Nature 489:52-55. [doi:10.1038/489052a]
Yoav Gilad
& Eran Segal

11 comments :

  1. It's my understanding that the theory that much of DNA was 'junk' was supported by two points. First, that is what would be expected from an evolutionary viewpoint. The 'junk' doesn't cost much if anything from the survival/reproduction standpoint; so one expects a certain accumulation. Second, different organisms that are phenotypically similar, e.g. two species of frog, may have vastly different amounts of 'junk' DNA; presumably due to different evolutionary exposures to viruses. But being a physicist I just have picked up these ideas from the popular literature and am in no position to actually evaluate them.

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    1. @Brent Meeker

      Two more points: Genetic Load and lack of conservation.

      I'm taking it from this comment:
      http://sandwalk.blogspot.com/2012/09/encode-leader-says-that-80-of-our.html?showComment=1346945434744#c8273351160324491076

      See this article:
      http://sandwalk.blogspot.com/2009/11/genetic-load-neutral-theory-and-junk.html

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    2. The 'junk' doesn't cost much if anything from the survival/reproduction standpoint; so one expects a certain accumulation.

      On its own, that's not a good argument - why are bacteria devoid of junk if it was just about that?

      Second, different organisms that are phenotypically similar, e.g. two species of frog, may have vastly different amounts of 'junk' DNA; presumably due to different evolutionary exposures to viruses

      For very closely related species, it is very often polyploidy that's responsible, i.e think of Xenopus laevis vs tropicalis. It has to be an extremely dramatic post-divergence selfish element proliferation for large differences in genome size to accumulate between closely related genes, that follows directly from the definition of "closely related". And that's not seen that often

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  2. @Atheistoclast,

    'Du-uh, of course multicellular, eukaryotic regulation is going to be fundamentally different from prokaryotic regulation'

    why 'of course'?

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  3. I think we actually have a pretty good understanding of gene regulation in eukaryotes. It's a model that seems to work well for most genes.

    You and the authors are talking about two different things. You're saying we have a good idea how eukaryotic genes are regulated (enhancers, long-range interactions, etc) from extensive studies of a few genes (e.g. the hemoglobin cluster). This is true. The authors are saying, if you take a random gene in the human genome, you have no idea where the enhancers are, and it's tough to figure it out without time-consuming studies. This is also true; ENCODE was designed to address the latter--they want to create a reference genome annotated with the "best guesses" of where enhancers (etc.) are for *every* gene.

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  4. Larry, science evolves. Atheists are losing their talking point about junk DNA. Get over it.

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    1. Anonymous, unfair. I am as critical of Larry as anyone here, but he hasn't at any point since the ENCODE article came out separated the issue from his scientific grounds for challenging it. He has repeatedly made the point that he sees this as a matter of science and not an ideological talking point.

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    2. Anonymous, there are 5-6 positive arguments that most of the genome must be non-functional.

      Address those positive arguments. Merely asserting that "atheists believe it" does not refute arguments from genetic load, C-value paradox, megabase deletion mouse, etc. Atheists also believe the Earth is round. Will you say it's flat just to tick them off?

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    3. Don't feed the trolls.

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